Abstract
GQEQSHQDEGVIVR (T9) is a peptide originated by the tryptic digestion of lupin β-conglutin that is absorbed in human intestinal Caco-2 cells. A previous study has shown that T9 impairs the protein–protein interaction between mutant D374Y Proprotein Convertase Subtilisin/Kexin 9 (PCSK9D374Y) and the low-density lipoprotein receptor (LDLR), thus exerting a hypocholesterolemic effect. Moreover, a bioinformatic study predicting that T9 may potentially act as an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCoAR), has suggested a complementary cholesterol-lowering activity. The present study demonstrates that T9 inhibits in vitro the HMGCoAR functionality with an IC50 value of 99.5 ± 0.56 µM. Through the inhibition of either HMGCoAR or PCSK9D374Y activities, T9 enhances the LDLR protein levels leading to an improved ability of HepG2 cells transfected with the mutant PCSK9D374Y-FLAG plasmid to uptake extracellular LDL with a final cholesterol-lowering effect. In addition, T9 modulates the PCSK9D374Y signaling pathway in transfected HepG2 cells leading to a decrease of PCSK9D374Y and HNF-1α protein levels. All these results indicate that the hypocholesterolemic effects of T9 are due to a dual mechanism of action involving either the modulation of the PCSK9D374Y or LDLR pathways. This may represent an added value from a therapeutic point of view.
Highlights
Reducing low-density lipoprotein cholesterol (LDL-C) is a priority in managing patients with severe hypercholesterolemia and at high risk of cardiovascular disease and disability [1]
All these results indicate that the hypocholesterolemic effects of T9 are due to a dual mechanism of action involving either the modulation of the PCSK9D374Y or low-density lipoprotein receptor (LDLR) pathways
We have demonstrated that P5 (LILPKHSDAD) and T9 are the first food-derived peptides able to affect the protein–protein interaction (PPI) between proprotein convertase subtilisin/kexin type 9 (PCSK9) and the LDLR, determining an increased ability of HepG2 cells to clear extracellular LDL [15]
Summary
Reducing low-density lipoprotein cholesterol (LDL-C) is a priority in managing patients with severe hypercholesterolemia and at high risk of cardiovascular disease and disability [1]. The traditional approach consists of inhibiting the activity of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCoAR), which is the rate-limiting enzyme of the cellular cholesterol biosynthetic pathway [2]. This approach represents an efficient way to reduce serum cholesterol levels through the increased ability of the LDL receptor (LDLR) to uptake extracellular LDL [3]. In this context, literature provides some examples of natural compounds targeting the HMGCoAR activity, such as lupin, soybean, and amaranth peptides, or monacolin K in red yeast rice extract [4,5,6,7]. The main role of PCSK9 is the degradation of LDLR protein with a subsequent increase of the LDL-C levels [9,10,11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
